Epidemiologic studies point to a complex association between alcohol and cardiovascular disease (CVD). Frequent moderate consumption of alcohol, e.g., 1-2 drinks per day, is a negative risk factor for atherosclerosis and its clinical sequelae myocardial infarction and ischemic stroke. On the other hand, binge drinking, i.e., consuming 5 or more drinks in a relatively short time period, is associated with increased CVD and associated mortality. The balance between alcohol and its primary metabolite, acetaldehyde, may be critical in mediating these seemingly opposite effects of the two drinking patterns. In agreement with epidemiologic studies, striking differential effects of daily moderate and binge alcohol (ethanol, EtOH) consumption on atherosclerotic plaque development, cholesterol levels and weight gain in a mouse model have recently been described. Intriguingly, the precise signaling and molecular mechanisms whereby alcohol elicits its cardiovascular effects, good and bad, have not yet been elucidated. One potentially novel target for alcohol is the Notch signaling pathway, as it is emerging that Notch plays a pivotal role in the differentiation of adul vascular smooth muscle cells (SMC), whose growth and migration are key processes in the pathophysiology of atherosclerosis and in restenosis. The expression of several components of the Notch pathway are enhanced following experimentally induced vascular injury while preferential inhibition of Notch 1, rather than Notch 3 attenuates neointimal formation. This lab's recently published data support an inhibitory effect of daily moderate alcohol treatment on SMC Notch 1 receptor levels and downstream target gene expression, concomitant with inhibition of SMC proliferation in vitro and marked attenuation of neointimal development and medial thickening in vivo. Interestingly, differential effects of alcohol and its metabolite, acetaldehyde on monocyte function have been reported. Moreover, our preliminary data now suggest that in apparent contrast to ethanol, acetaldehyde stimulates Notch expression and proliferation in SMC. Therefore, the central hypothesis of our application is that 'daily moderate' and 'binge' alcohol consumption have opposite effects on atherosclerotic plaque development mediated by differential effects of ethanol (anti-atherogenic), and its metabolite acetaldehyde (pro-atherogenic), on Notch signaling in vascular SMC. Because the mortality from cardiovascular disease is so high, deciphering the mechanisms whereby alcohol can either protect or exacerbate it is clearly of major clinical importance and significance.